This invention is directed to a class of binding ligands for cocaine receptors, neurotransmitter transporters and other receptors, neurotransmitter transporters in the brain. Specifically, a novel family of compounds shows high binding specificity and activity, and, in a radiolabeled form, can be used to bind to these receptors, for biochemical assays and imaging techniques. Such imaging is useful for determining effective doses of new drug candidates in human populations. In addition, the high specificity, slow onset and long duration of the action of these compounds at the receptors makes them particularly well suited for therapeutic uses, for example as substitute medication for psychostimulant abuse. Some of these compounds may be useful in treating Parkinson""s Disease, attention deficit hyperactivity disorder, bipolar disorder, eating disorders, obesity, panic attacks and disorders, obsessive-compulsive disorder, cocaine, nicotine and alcohol addiction or depression, by virtue of their inhibitory properties at monoamine transporters.
This application claims priority, inter alia, from of U.S. patent application Ser. No. 07/972,472 filed Mar. 23, 1993, now U.S. Pat. No. 5,413,779, the entirety of which is incorporated by reference. This application also claims priority from U.S. patent application Ser. No. 07/564,755, now U.S. Pat. No. 5,128,118, and U.S. PCT Application PCT/US91/05553 (the U.S. National Phase of which is U.S. Ser. No. 07/972,472), filed Aug. 9, 1991, both applications being incorporated herein by reference. In U.S. application Ser. No. 07/564,755, there is disclosure of a family of compounds exhibiting particularly high specificity and affinity for cocaine receptors and other neurotransmitter receptors in the brain of the formula: 
Where the broken line represents an optional chemical bond and the substituents at 2 and 3 may be at any position;
The iodo substituent may be at o, m, A, or multisubstituted;
R1=CH3, CH2CHxe2x95x90CH2, (CH2)nC6H5 n=1-4;
R2=CH3, C2H5, CH3(CH2)3, (CH3)2CH, C6H5, C6H5CH2, C6H5(CH2)2;
X=pharmacologically acceptable anion
Sites of specific interest included cocaine receptors associated with dopamine (DA) transporter sites.
Subsequently, in the U.S. PCT Application from which priority is claimed, and which is incorporated herein by reference, the values for R1 and R2 were expanded, such that R1 may be an alkyl of 1-7 carbon atoms, CH2CR3xe2x95x90CR4R5 wherein R3-R5 are each, independently C1-6 alkyl, or phenyl compounds of the formula C6H5(CH2)y, wherein y=1-6. R2 may be any of those list above and also C6H5(CH2)z, wherein z=1-6. The PCT filing also reveals the affinity of these compounds for cocaine receptors associated with serotonin (5-hydroxytryptamine, 5-HT) transporters, and confirms, for the first time, that the in vitro binding reported in the earlier-filed application, is confirmed in in vivo testing. Specific disclosure for a variety of applications, including using the compounds in both PET and SPECT scanning, wherein either the iodine substituent, or one of the carbon groups is radioactive (I-123, 125 or 131 and C-11) thus providing methods for scanning for the presence of specific cocaine receptors. Such scanning processes may be used to determine physiological conditions associated with dopamine and serotonin re-uptake inhibitors, which are or lead to behavioral and neurodegenerative disorders/diseases. Such disorders include depression, bipolar disorder, eating disorders, obesity, attention deficit disorder, panic attacks and disorders, obsessive-compulsive disorder, Parkinson""s Disease, and cocaine, nicotine and alcohol addiction. These compounds, in addition to being used in treatment of these disorders, may be used to examine in general the density and distribution of specific cocaine receptors in various parts of the brain and/or body, to determine the efficacy of neurological treatments aimed at halting or reversing the degeneration of specific nerves in the brain, and for screening drugs, such as antidepressant drugs. The imaging techniques may also be used to determine the doses of novel or potential therapeutic agents that occupy significant quantities of receptors by in vivo competition technique.
The affinity and specificity of these compounds, as reported in the applications incorporated, is surprisingly high, and compared with prior art compounds, such as [3H]WIN 35,428, the novel compounds of these applications exhibit extremely low IC50 values for binding inhibition.
In U.S. patent application Ser. No. 08/164,576, filed Dec. 10, 1993, now U.S. Pat. No. 5,496,953, also incorporated herein by reference in its entirety, a family of compounds was disclosed, having the formula: 
wherein
Y is CONRR2,
R1 is hydrogen or C1-5 alkyl,
X is H, C1-6 alkyl, C3-8 cycloalkyl, C1-4 alkoxy, C1-6 alkynyl, halogen amino or acylamido,
R and R2 independently are H, C1-6 alkyl, alkene or alkyne, phenyl, phenyl substituted with 1-3 of C1-6 alkyl, alkene, alkyne or alkoxy, C1-6 alkoxy, phenoxy, amine amino substituted with 1 or 2 C1-6 alkyl, alkene, alkyne, alkoxy, phenyl or phenoxy, or R and R2 may combine to form a cyclic structure selected from the group consisting of pyrrolidinyl, morpholinyl and piperidinyl moieties, and
Z is H, I, Br, Cl, F, CN, CF3, NO2, N3, OR1, CO2NH2, CO2R1, C1-6 alkyl, NR4R5, NHCOF5, NHCOR6, wherein R4-R6 are each C1-6 alkyl.
These compounds exhibit unusually high affinity and specificity for binding to receptors for the dopamine transporter site, as well as the serotonin transporter site, based on inhibition of [3H]paroxetine binding. This high affinity makes certain of these compounds particularly well suited for use as therapeutic agents, as well as for imaging agents for dopamine and serotonin transporters.
Accordingly, one object of this invention is to provide novel compounds which bind to cocaine receptors which include neurotransmitter transporters.
Another object of the invention is to provide novel 3-(substituted phenyl)-2-(substituted)tropane analogs which bind to cocaine receptors.
Still another object of the invention is to provide 3-(substituted phenyl)-2-(substituted)tropane analogs which bind preferentially to the dopamine transporter.
Yet another object of the invention is to provide 3-(substituted phenyl)-2-(substituted)tropane analogs which bind preferentially to the serotonin transporter.
Another object of the invention is to provide a compound of the formula 
wherein R is CH3, C2H5, CH2CH2CH3, or CH(CH3)2, R1 is CH3, CH2CH5, (CH2)2C6H5, (CH2)3C6H5, or 
wherein X is H, OCH3, or Cl and Y is H, OCH3, CO2CH3 or Cl, and n=1-8.
Another object of the invention is to provide compounds having the following formulas: 
wherein
R1=hydrogen, C1-5 alkyl,
X=H, C1-6 alkyl, C3-8 cycloalkyl, C1-4 alkoxy, C1-6 alkynyl, halogen, amino, acylamido, and
Z=H, I, Br, Cl, F, CN, CF3, NO2, N3, OR1, CONH2, CO2R1, C1-6 alkyl, NR4R5, NHCOR5, NHCO2R6,
Rb is C1-6 alkyl, C1-6 alkenyl, phenyl, or phenyl substituted with C1-6 alkyl, C1-6 alkoxy, or halogen; 
wherein R1=H or CO2CH3; 
wherein R1, R2=H or CH3 and X=CH3; 
wherein R=H, CH3 or CH2CO2C2H5, 
and Y=H, X=CH3, Cl, t-CH3CHxe2x95x90CHxe2x80x94, 2-naphthyl, or H2Cxe2x95x90Cxe2x80x94; 
wherein R=CH3, C6H5, 4-CH3OC6H4, 4-ClC6H4, 4-BrC6H4, or (CH3)2CH and X=Cl, CH3 or H; and 
wherein X=CH3 or H and Y=H or CH3.
A further object of the invention is to provide a method for treating psychostimulant abuse, by administering to a patient in need of such treatment a pharmaceutically effective amount of a 3-(substituted phenyl)-2-(substituted)tropane analog.
A still further object of the invention is to provide method for inhibiting the action of a psychostimulant, by administering to a patient in need of such treatment a psychostimulant-inhibiting amount of a 3-(substituted phenyl)-2-(substituted)tropane analog.
Still another object of the invention is to provide a method for inhibiting neurotransmitter re-uptake by administering to a patient in need of such treatment a neurotransmitter transporter-inhibiting amount of a 3-(substituted phenyl)-2-(substituted)tropane analog.
Another object of the invention is to provide a method for treating neurodegenerative disorders, by administering to a patient in need of such treatment a pharmaceutically effective amount of a 3-(substituted phenyl)-2-(substituted)tropane analog.
A further object of the invention is to provide binding ligands for in vitro or in vivo studies, to measure doses, concentrations and receptor occupancy, or to screen for new drugs acting at these sites.
Still another object of the invention is to provide a method for treating depression, by administering to a patient in need of such treatment a pharmaceutically effective amount of a 3-(substituted phenyl)-2-(substituted)tropane analog.
Briefly, the invention pertains to the discovery that certain cocaine analogs are particularly well suited for therapeutic use as neurochemical agents. These particular cocaine analogs, in modulating neurotransmitter actions, may also be useful for modulating the actions of pyschostimulant drugs, for modulating endocrine function, for modulating motor function, and for modulating complex behaviors.
With the foregoing and other objects, advantages and features of the invention that will become here in after apparent, the nature of the invention may be more clearly understood by reference to the following detailed description of the preferred embodiments of the invention and to the appended claims.